Abstract
Lymphangioleiomyomatosis (LAM) is a rare lung-metastasizing neoplasm caused by the proliferation of smooth muscle-like cells that commonly carry loss-of-function mutations in either the tuberous sclerosis complex 1 or 2 (TSC1 or TSC2) genes. While allosteric inhibition of the mechanistic target of rapamycin (mTOR) has shown substantial clinical benefit, complementary therapies are required to improve response and/or to treat specific patients. However, there is a lack of LAM biomarkers that could potentially be used to monitor the disease and to develop other targeted therapies. We hypothesized that the mediators of cancer metastasis to lung, particularly in breast cancer, also play a relevant role in LAM. Analyses across independent breast cancer datasets revealed associations between low TSC1/2 expression, altered mTOR complex 1 (mTORC1) pathway signaling, and metastasis to lung. Subsequently, immunohistochemical analyses of 23 LAM lesions revealed positivity in all cases for the lung metastasis mediators fascin 1 (FSCN1) and inhibitor of DNA binding 1 (ID1). Moreover, assessment of breast cancer stem or luminal progenitor cell biomarkers showed positivity in most LAM tissue for the aldehyde dehydrogenase 1 (ALDH1), integrin-ß3 (ITGB3/CD61), and/or the sex-determining region Y-box 9 (SOX9) proteins. The immunohistochemical analyses also provided evidence of heterogeneity between and within LAM cases. The analysis of Tsc2-deficient cells revealed relative over-expression of FSCN1 and ID1; however, Tsc2-deficient cells did not show higher sensitivity to ID1-based cancer inhibitors. Collectively, the results of this study reveal novel LAM biomarkers linked to breast cancer metastasis to lung and to cell stemness, which in turn might guide the assessment of additional or complementary therapeutic opportunities for LAM.
Highlights
LAM is a rare lung disease that appears predominantly in women of childbearing age and is depicted by cystic lung destruction [1,2,3,4]
Low TSC2 expression was found to be significantly associated with lung but not bone metastasis events in the analysis of a seminal breast cancer dataset [27] (Fig 1A)
Consistent with clinical observations [36], lung metastatic events were preferentially linked to estrogen receptor alpha (ERa)-negative tumors (Fig 1B) and the above association was significant in this subtype (P = 0.029)
Summary
LAM is a rare lung disease that appears predominantly in women of childbearing age and is depicted by cystic lung destruction [1,2,3,4]. LAM results from the proliferation of typically estrogen receptor alpha (ERa)- and progesterone receptor (PR)-positive smooth muscle-like cells [5,6,7] with lung metastatic potential [8,9]. LAM cells commonly carry loss-offunction mutations in either the TSC1 or TSC2 tumor suppressor gene [10,11,12,13] and, exhibit abnormal activation of mTORC1 [14,15]. A specific cell type(s) may possess metastatic potential with lung tropism when, most commonly, a TSC1 or TSC2 mutation is acquired and mTORC1 is abnormally activated. There are recorded cases of sporadic LAM without mutations in TSC1 or TSC2 and, without abnormal activation of mTORC1 [22]
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