DNA mismatch repair and the transition to hormone independence in breast and prostate cancer

Abstract

The molecular basis for the progression of breast and prostate cancer from hormone dependent to hormone independent disease remains a critical issue in the management of these two cancers. The DNA mismatch repair system is integral to the maintenance of genomic stability and suppression of tumorigenesis. No firm consensus exists regarding the implications of mismatch repair (MMR) deficiencies in the development of breast or prostate cancer. However, recent studies have reported an association between mismatch repair deficiency and loss of specific hormone receptors, inferring a potential role for mismatch repair deficiency in this transition. An updated review of the experimental data supporting or contradicting the involvement of MMR defects in the development and progression of breast and prostate cancer will be provided with particular emphasis on their implications in the transition to hormone independence.

Introduction

Breast cancer is both the most prevalent cancer and the leading cause of cancer-related mortality in women worldwide [1]. Prostate cancer is the most commonly diagnosed malignancy in men in the United States, second only to lung cancer in cancer-related deaths [2]. These cancers are not only similar in their epidemiological patterns, but also possess similar molecular mechanisms of pathogenesis and disease progression. Both breast and prostate cancer are hormone-related diseases. Steroid hormones, such as oestrogen, progesterone, and androgen as well as exogenous hormones contribute to the initiation and promotion of multistage carcinogenesis via specific steroid hormone receptors [3]. Hormone deprivation therapies inhibit cell growth and have provided significant improvements in survival in both diseases. Currently, anti-oestrogens are the most effective treatment option for women with oestrogen receptor (ER) positive breast cancer, while androgen deprivation therapy is the prime therapeutic approach for men with advanced prostate cancer. However, hormone resistance remains a significant clinical problem and limits the benefits of these therapies in a considerable proportion of initially drug-responsive patients [4], [5], [6]. To date, curative treatments for advanced stages of both cancers are lacking. Indeed, an understanding of the underlying molecular mechanisms involved in the transition to hormone refractory disease is vital for the development of effective therapeutic and preventive strategies to combat these malignancies.

A large and compelling body of epidemiological and experimental data implicates oestrogen in the pathogenesis of breast and endometrial cancer (for review see [3], [7]). Similarly, androgens have been recognised to play an important role in controlling the growth of the normal prostate gland, and in promoting benign prostate hyperplasia and prostatic carcinoma [8], [9], [10] however unlike breast cancer, serum sex hormone levels appear unrelated to prostate cancer risk [11]. The most commonly accepted risk factors for breast cancer include early menarche, late menopause, alcohol consumption, post-menopausal obesity and hormone replacement therapy [3]. Each of these risk factors increases one’s exposure to hormones. Hormones stimulate cell proliferation and thus increased exposure to these hormones promotes the opportunity to develop and accumulate random genetic errors. While a number of select candidate genes have been identified as biomarkers for breast and prostate cancer (such as those involved in hormone biosynthesis, activation, inactivation and transport) [12], [13], the molecular mechanisms involved in the progression to hormone independent disease are less well-understood.

Random genetic errors due to this increased proliferation occur simultaneously in genes not related to hormone manipulation and can drastically reduce a cell’s capacity for self-protection against random excitotoxic, metabolic and oxidative insults. Mutations in DNA repair genes have been associated with a mutator phenotype and confer resistance to cancer therapies [14], [15], [16]. In particular, the role of defects in DNA mismatch repair (MMR) genes in the pathogenesis of breast and prostate cancer has been investigated in the last decade. In this review, we will describe the experimental data supporting or contradicting the involvement of MMR defects in the development of breast and prostate cancer. In addition, we will explore the possible role of MMR deficiency in the transition to hormone independence. A number of recent observations imply a direct role for oestrogen in the regulation of MMR activity, but how this may relate to disease progression and what this may imply in terms of the mechanisms of androgen independence are unclear.